Structure lithium enolates

A more detailed representation of the reaction requires more intimate knowledge of the enolate structure. Studies of ketone enolates in solution indicate that both tetrameric and dimeric clusters can exist Tetrahydrofliran, a solvent in which many synthetic reactions are performed, favors tetrameric structures for the lithium enolate of isobutyr-ophenone, for example. ... 

Compare the geometries of the cyclohexanone enolate and the cyclohexanone lithium enolate. Do both molecules show delocalized structures, or is the bonding in one of them more localized For comparison, examine the geometries of 1-hydroxycyclohexene md cyclohexanone. 

Examine the eleetrostatic potential map of eaeh nueleophile (enamine, silyl enol ether, lithium enolate and enol) with emphasis on the face of the nucleophilic alkene carbon. Rank the nucleophiles from most electron rich to least electron rich. What factors are responsible for this order (Hint For each molecule, consider an alternative Lewis structure to that given above that places a negative charge on the nucleophilic carbon.)... 

Reaction of lithium enolate 2 with prochiral 3-buten-2-one (4) proceeds with minimal selectivity to produce nearly equal amounts of the two diastereomers of structure 540,41. 

The reaction of the enamines of cyclohexanones with a,ft-unsaluraled sulfones gives mixtures resulting from attack of the enamine at the a- and /(-carbons of the oc,/ -unsaturated sulfone. The ratio of x- and /1-adducts is dependent upon the reaction solvent, the geometry and structure of the sulfone1 4. The diastereoselectivity of these reactions is also poor. The reaction of lithium enolates of cyclic ketones with ( )-[2-(methylsulfonyl)ethenyl]benzene, however, gives bicyclic alcohols, as single diastereomers, that result from initial -attack on the oc,/ -unsaturated sulfone5. 

Fig. 1.1. Crystal structure of lithium enolate of methyl -butyl ketone in a structure containing four Li+, two enolates, and one HMDA anions, one bromide ion, and two TMEDA ligands. Reproduced from Angew. Chem. Int. Ed. Engl., 35, 1322 (1996), by permission of Wiley-VCH.

The reactants are usually /V-acyl derivatives. The lithium enolates form chelate structures with Z-stereochemistry at the double bond. The ring substituents then govern the preferred direction of approach. 

Aldol Reactions of Boron Enolates. The matter of increasing stereoselectivity in the addition step can be addressed by using other reactants. One important version of the aldol reaction involves the use of boron enolates.15 A cyclic TS similar to that for lithium enolates is involved, and the same relationship exists between enolate configuration and product stereochemistry. In general, the stereoselectivity is higher than for lithium enolates. The O-B bond distances are shorter than for lithium enolates, and this leads to a more compact structure for the TS and magnifies the steric interactions that control stereoselectivity. 

Fig. 2.6. Free-energy profile (B3LYP/6-31 + G with ZPE correction) for intermediates and transition structures for Wadsworth-Emmons reactions between the lithium enolate of trimethyl phosphonoacetate anion and formaldehyde in the gas phase and in tetrahydrofuran or ethanol. Adapted from J. Org. Chem., 63, 1280 (1998), by permission of the American Chemical Society.

The ester 7-1 gives alternative stereoisomers when subjected to Claisen rearrangement as the lithium enolate or as the silyl ketene acetal. Analyze the respective transition structures and develop a rationale to explain these results. 

Detailed investigations indicate that the enolization process (LDA, THF) affords enolates 37 and 38 with at/east 97% (Z)-stereoselection. Related observations have recently been reported on the stereoselective enolization of dialkylthioamides (38). In this latter study, the Ireland-Claisen strategy (34) was employed to assign enolate geometry. Table 10 summarizes the enolization stereo selection that has been observed for both esters and amides with LDA. Complementary kinetic enolization ratios for ketonic substrates are included in Table 7. Recent studies on the role of base structure and solvent are now beginning to appear in the literature (39,40), and the Ireland enolization model for lithium amide bases has been widely accepted, A tabular survey of the influence of the ester moiety (ORj) on a range of aldol condensations via the lithium enolates is provided in Table 11 (eq. [24]). Enolate ratios for some of the condensations illustrated may be found in Table 10. It is apparent from these data that ( )-enolates derived from alkyl propionates (Rj = CH3, t-C4H9) exhibit low aldol stereoselectivity. In contrast, the enolates derived from alkoxyalkyl esters (Rj = CHjOR ) exhibit 10 1 threo diastereo-... 

In 1998, Hasanayn and Streitwieser reported the kinetics and isotope effects of the Aldol-Tishchenko reaction . They studied the reaction between lithium enolates of isobu-tyrophenone and two molecule of beuzaldehyde, which results iu the formation of a 1,3-diol monoester after protonation (Figure 28). They analyzed several aspects of this mechanism experimentally. Ab initio molecular orbital calculatious ou models are used to study the equilibrium and transition state structures. The spectroscopic properties of the lithium enolate of p-(phenylsulfonyl) isobutyrophenone (LiSIBP) have allowed kinetic study of the reaction. The computed equilibrium and transition state structures for the compounds in the sequence of reactions in Figure 28 are given along with the computed reaction barriers and energy in Figure 29 and Table 6. 

The excellent agreement with the experimental and calculated isotope effect (calculated for formaldehyde, 3.22, and for acetaldehyde, 3.3 experimental value 2.9) supports the computational approach. This suggests that the computed transition structure for hydride transfer in the reaction of the lithium enolate of acetone with acetaldehyde (Figure 30) is realistic. 

Experimentally, x values for gaseous lithium halides were determined as early as 1949 by molecular beam resonance experiments In solution, the quadrupolar interaction of ethyUithium and of t-butyllithium were investigated in 1964 . It was found that tetrameric and hexameric aggregates have different interactions. In the solid state x of tetrameric methyl- and ethyUithium was determined in 1965 and 1966 , and for lithium formate in 1972 . However, it was not untU Jackman started his investigations of lithium enolates and phenoxides in solution that the quadrupolar interaction was used in a systematic fashion to obtain structural information . 

Jackman and Szeverenyi were the first to systematically correlate the quadrupoiar interaction with molecular structure, i.e. with the aggregation of lithium enolates ". They noted that a tetrameric aggregate had a smaller QSC than a dimeric aggregate, ca 135 kHz compared to an estimate of 230 kHz for the dimer. The QSC of the tetramer was shown to be of the same magnitude in three different ethereal solvents. 

A method for enantioselective synthesis of carboxylic acid derivatives is based on alkylation of the enolates of /V-acyl oxazolidinones.59 The lithium enolates have the structures shown because of the tendency for the metal cation to form a chelate. 

The opportunity for chelation in the various enolate intermediates offers a possible explanation for the observed diastereoselectivities. In the dianions derived from l-acyl-2-pyrrolidinemethanols strong chelation of both of the lithium cations should lead to a rigid enolate structure 9. It is reasonable to assume that the pyrrolidine ring is locked in one conformation. Since, according to models, it is difficult to attribute the observed high diastereoselectivity to steric hindrance, it is probable that the lone pair on the nitrogen directs the facial selectivity of electrophilic attack (see Section 1.1.1.3.3.1.) to one side of the enolate a-carbon. 

On the other hand, the O-metallated structure E is also observed, for example when a zinc enolate is prepared by transmetallation of a lithium enolate with a Zn(II) salt5. 

Carboxylic acids can be alkylated in the a position by conversion of their salts to dianions [which actually have the enolate structures RCH=C(0 )21497] by treatment with a strong base such as lithium diisopropylamide.1498 The use of Li as the counterion is important, because it increases the solubility of the dianionic salt. The reaction has been applied1499 to primary alkyl, allylic, and benzylic halides, and to carboxylic acids of the form RCHjCOOH and RR"CHCOOH.1454 This method, which is an example of the alkylation of a dianion at its more nucleophilic position (see p. 368), is an alternative to the malonic ester synthesis (0-94) as a means of preparing carboxylic acids and has the advantage that acids of the form RR R"CCOOH can also be prepared. In a related reaction, methylated aromatic acids can be alkylated at the methyl group by a similar procedure.1500... 

Notably, the lithium enolates have the planar methylenecyclopropane-type structure56, but give C-alkylation products49"52. X-ray structure analysis of the lithium enolate56 and bicyclobutyllithium57 TMEDA complexes revealed that both crystallize as lithium bridging dimers. 

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